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Supplemental Digital Content is available in the text.The breast is a rare site for metastases, and their molecular characteristics have not been studied yet. Intrinsic molecular genetics, cancer characteristics, and breast tissue immune responses in diverse metastases to the breast have not been previously studied. We identified 64 patients with cancers metastatic to the breast: 51 carcinomas and 13 melanomas. Programmed death ligand 1 (PD-L1), steroid receptors, and HER2/neu expressions were evaluated using immunohistochemistry. Gene sequencing, copy number alterations, microsatellite instability, and tumor mutational burden were performed using next-generation sequencing platforms. The 3 most common primary sites for metastatic carcinomas were lung (37%), ovary (29%), and fallopian tubes/peritoneum (14%). TP53mutations were commonly (50%) observed among the carcinoma cases, while other mutations were characteristic for the primary cancers (VHLin renal, BRCA1in the fallopian tube, and BRAFin melanomas). High tumor mutational burden was detected in 5/14 carcinomas and 3/7 melanomas. Tumor cell PD-L1 expression was detected in 6 carcinomas, but not in any of the melanomas, whereas immune cells’ expression of PD-L1 was seen in 17 carcinomas and 6 melanomas. Estrogen receptor status was positive in 13/49 carcinomas including 12 adenocarcinomas originating from the ovary and fallopian tube or peritoneum and 1 duodenal neuroendocrine carcinoma. No carcinoma was HER2/neu positive. Intrinsic genetic characteristics of the metastases to the breast followed the pattern commonly seen in primary tumors. Biomarkers of potential benefit to immune checkpoint inhibition therapy were limited to PD-L1-positive non–small cell lung cancer. No common characteristics of the heterogeneous group of tumor metastases to this organ were identified.

Worldwide, millions of women live with breast implants. Therefore, it is important that physicians be aware of an uncommon but possibly serious complication arising from breast implants: breast implant–associated anaplastic large cell lymphoma (BIA-ALCL). Breast implant–associated anaplastic large-cell lymphoma most commonly presents as a delayed fluid collection around a textured breast implant or as a mass in the capsule surrounding the implant. The exact pathogenesis of the disease remains unclear. The neoplastic cells of BIA-ALCL show strong uniform staining for CD30 and are consistently negative for activin receptor-like kinase 1. Patients with confirmed cases should be referred to a lymphoma specialist or breast medical oncologist for a complete oncologic evaluation before any surgical intervention. For disease confined to the fluid accumulation or capsule, or both, surgical removal of the implant and complete capsulectomy is the preferred treatment. Postoperative chemotherapy or radiation, or both, are not considered necessary for patients with limited-stage disease and are reserved for advanced disease stages. Generally, BIA-ALCL is a local disease that follows an indolent course and has an excellent prognosis. Although complete remission of disease has occurred in patients with BIA-ALCL, median overall survival is reduced. As of March 2018, approximately 529 unique, confirmed BIA-ALCL cases had been reported in 23 countries. To date, 16 patients have died from BIA-ALCL, and all had extracapsular involvement. The aim of this article is to summarize the diagnosis, evaluation, and management of BIA-ALCL, based on established guidelines, for all practitioners who may care for patients with breast implants.

Supplemental digital content is available in the text.

Flat epithelial atypia and atypical ductal hyperplasia historically have undergone surgical excision due to their potential for upgrade to malignancy, but emerging evidence suggests that a tailored management approach with observation may be appropriate in certain patients to reduce overtreatment.

The amplification of chromosome 9p24.1 encoding PD-L1, PD-L2, and JAK2 has been reported in multiple types of cancer and is associated with poor outcome, upregulation of PD-L1, and activation of the JAK/STAT pathway. We have developed a novel fluorescence in situ hybridization assay which combines 3 probes mapping to 9p24.1 with a commercial chromosome 9 centromere (CEN9) probe for detection of the JAK2/9p24.1 amplification. JAK2 fluorescence in situ hybridization was compared with array-based comparative genomic hybridization in 34 samples of triple negative breast cancer tumor. By array-based comparative genomic hybridization, 15 had 9p24.1 copy-number gain (log2ratio>0.3) and 19 were classified as non-gain (log2ratio≤0.3). Copy-number gain was defined as JAK2/CEN9 ratio ≥1.1 or average JAK2 signals≥3.0. Twelve of 15 samples with copy-number gain by array-based comparative genomic hybridization were also detected by fluorescence in situ hybridization. Eighteen of 19 samples classified as copy-number non-gain by array-based comparative genomic hybridization were concordant by array-based comparative genomic hybridization. The sensitivity and specificity of the fluorescence in situ hybridization assay was 80% and 95%, respectively (P=0.02). The sample with the highest level of amplification by array-based comparative genomic hybridization (log2ratio=3.6) also scored highest by fluorescence in situ hybridization (ratio=8.2). There was a correlation between the expression of JAK2 and amplification status (Mean 633 vs 393, P=0.02), and there was a trend of association with PD-L1 RNA expression (Mean 46 vs 22, P=0.11). No significant association was observed between PD-L1 immunohistochemistry expression and copy-number gain status. In summary, the novel array-based comparative genomic hybridization assay for detection of chromosome 9p24.1 strongly correlates with the detection of copy-number gain by array-based comparative genomic hybridization. In triple negative breast cancer, this biomarker may identify a relevant subset of patients for targeted molecular therapies.

The amplification of chromosome 9p24.1 encoding PD-L1, PD-L2,and JAK2has been reported in multiple types of cancer and is associated with poor outcome, upregulation of PD-L1, and activation of the JAK/STAT pathway. We have developed a novel fluorescence in situhybridization assay which combines 3 probes mapping to 9p24.1 with a commercial chromosome 9 centromere (CEN9) probe for detection of the JAK2/9p24.1 amplification. JAK2 fluorescence in situhybridization was compared with array-based comparative genomic hybridization in 34 samples of triple negative breast cancer tumor. By array-based comparative genomic hybridization, 15 had 9p24.1 copy-number gain (log2ratio>0.3) and 19 were classified as non-gain (log2ratio≤0.3). Copy-number gain was defined as JAK2/CEN9 ratio ≥1.1 or average JAK2 signals≥3.0. Twelve of 15 samples with copy-number gain by array-based comparative genomic hybridization were also detected by fluorescence in situhybridization. Eighteen of 19 samples classified as copy-number non-gain by array-based comparative genomic hybridization were concordant by array-based comparative genomic hybridization. The sensitivity and specificity of the fluorescence in situhybridization assay was 80% and 95%, respectively (P=0.02). The sample with the highest level of amplification by array-based comparative genomic hybridization (log2ratio=3.6) also scored highest by fluorescence in situhybridization (ratio=8.2). There was a correlation between the expression of JAK2 and amplification status (Mean 633 vs393, P=0.02), and there was a trend of association with PD-L1 RNA expression (Mean 46 vs22, P=0.11). No significant association was observed between PD-L1 immunohistochemistry expression and copy-number gain status. In summary, the novel array-based comparative genomic hybridization assay for detection of chromosome 9p24.1 strongly correlates with the detection of copy-number gain by array-based comparative genomic hybridization. In triple negative breast cancer, this biomarker may identify a relevant subset of patients for targeted molecular therapies.

Linitis plastica (LP), a subset of gastric adenocarcinoma (GA), has been considered as a fatal disease with few management options. Little evidence has been reported regarding the role for surgical therapy in treating LP. A retrospective review of GA patients with LP from the surveillance, epidemiology, and end results database (2004–2009) was performed. 29,440 patients with GA were identified, of whom 948 (3.2%) had LP. After matching for American Joint Commission on Cancer (AJCC) stage, LP patients had significantly worse 5-year disease specific survival (DSS) compared with GA (6 vs 34%, P < 0.001). For potentially resectable LP patients (i.e., stage I–III), 5-year DSS was 0 per cent for no treatment and for radiation therapy alone, 18 per cent for both and surgery and radiation, and 20 per cent for surgery alone(P < 0.001). LP is a marker of poor survival in patients with GA. However, surgical resection provides the best oncologic outcomes in these patients with a 20 per cent 5-year DSS in patients with loco-regional disease.

Genome-wide fragmentation patterns in cell-free DNA (cfDNA) in plasma are strongly influenced by cellular origin due to variation in chromatin accessibility across cell types. Such differences between healthy and cancer cells provide the opportunity for development of novel cancer diagnostics. Here, we investigated whether analysis of cfDNA fragment end positions and their surrounding DNA sequences reveals the presence of tumor-derived DNA in blood. We performed genome-wide analysis of cfDNA from 521 samples and analyzed sequencing data from an additional 2147 samples, including healthy individuals and patients with 11 different cancer types. We developed a metric based on genome-wide differences in fragment positioning, weighted by fragment length and GC content [information-weighted fraction of aberrant fragments (iwFAF)]. We observed that iwFAF strongly correlated with tumor fraction, was higher for DNA fragments carrying somatic mutations, and was higher within genomic regions affected by copy number amplifications. We also calculated sample-level means of nucleotide frequencies observed at genomic positions spanning fragment ends. Using a combination of iwFAF and nine nucleotide frequencies from three positions surrounding fragment ends, we developed a machine learning model to differentiate healthy individuals from patients with cancer. We observed an area under the receiver operative characteristic curve (AUC) of 0.91 for detection of cancer at any stage and an AUC of 0.87 for detection of stage I cancer. Our findings remained robust with as few as 1 million fragments analyzed per sample, demonstrating that analysis of fragment ends can become a cost-effective and accessible approach for cancer detection and monitoring.

We conducted a multicenter phase II trial to assess the efficacy and toxicity of docetaxel and carboplatin combination as neoadjuvant therapy for stage II or III breast cancer (BC).

Excisional biopsy has been recommended for papillary lesions diagnosed on core needle biopsy (CNB) because a significant proportion of cases are upstaged to in situ/invasive cancer after surgical excision. The study goals were to identify patients at lowest risk of upstaging in whom excisional biopsy may potentially be avoided. We retrospectively evaluated 46 patients with a papillary lesion on CNB. Six patients were upstaged overall (13%), to intraductal papillary carcinoma (7%), invasive papillary carcinoma (4%), and mixed invasive ductal/lobular carcinoma (2%). The upstaging rate for patients with atypia on CNB was higher than for patients without atypia (33 vs3%, P= 0.011). No patient younger than 65 years was upstaged to in situor invasive carcinoma, and the mean lesion size was also higher among patients who were upstaged (P> 0.05). Patients younger than 65 years with small papillary lesions lacking atypia on CNB may therefore represent a low-risk group that may be offered close clinical and radiologic follow-up.

Preoperative computed tomography has been used to facilitate deep inferior epigastric artery perforator (DIEAP) flap breast reconstruction. This study identifies the improvements in outcome that this may provide.

The transverse rectus abdominus muscle (TRAM) flap is one of the treatment options for breast reconstruction. TRAM flap reconstruction donor site herniation rates range from 1 to 8.8. Traditionally, these hernias were treated by an open primary repair with or without the addition of onlay mesh. We report laparoscopic approach to treat TRAM and deep inferior epigastric perforator flap (DIEP) harvest site hernias with mesh.

Cyclo-oxygenase (COX)-2 expression correlates directly with highly aggressive and metastatic breast cancer, but the mechanism underlying this correlation remains obscure. We hypothesized that invasive human breast cancer cells that over-express COX-2 have the unique ability to differentiate into extracellular-matrix-rich vascular channels, also known as vasculogenic mimicry. Vascular channels have been associated with angiogenesis without involvement of endothelial cells, and may serve as another mechanism by which tumor cells obtain nutrients to survive, especially in less vascularized regions of the tumor. To determine whether COX-2 regulates vascular channel formation, we assessed whether treatment with celecoxib (a selective COX-2 inhibitor) or silencing COX-2 synthesis by siRNA inhibits vascular channel formation by breast cancer cell lines. Cell lines were selected based on their invasive potential and COX-2 expression. Additionally, gene expression analysis was performed to identify candidate genes involved in COX-2-induced vascular channel formation. Finally, vascular channels were analyzed in surgically resected human breast cancer specimens that expressed varying levels of COX-2. We found that invasive human breast cancer cells that over-express COX-2 develop vascular channels when plated on three-dimensional matigel cultures, whereas non-invasive cell lines that express low levels of COX-2 did not develop such channels. Similarly, we identified vascular channels in high-grade invasive ductal carcinoma of the breast over-expressing COX-2, but not in low-grade breast tumors. Vascular channel formation was significantly suppressed when cells were treated with celecoxib or COX-2 siRNA. Inhibition of channel formation was abrogated by addition of exogenous prostaglandin E2. In vitroresults were corroborated in vivoin tumor-bearing mice treated with celecoxib. Using gene expression profiling, we identified several genes in the angiogenic and survival pathways that are engaged in vascular channel formation. Antivascular therapies targeting tumor cell vasculogenic mimicry may be an effective approach to the treatment of patients with highly metastatic breast cancer.

Background:Patients diagnosed with melanoma of the foot have been reported to have a poor prognosis. We reviewed our experience at a tertiary-care medical clinic to determine the disease course in patients diagnosed with melanoma of the foot. Methods:A retrospective review was performed of 38 patients with a diagnosis of primary or locally recurrent melanoma of the foot treated between January, 1988, and July, 2004. The main outcome measures included methods of diagnosis, clinical and histopathologic features, and patterns of recurrence. Results:The mean age at diagnosis was 61 years; most were women (58%) and Caucasian (95%). The average time to diagnosis was 17 months. Initial clinical diagnosis had been considered benign in 12 (32%). The median Breslow thickness was 1.75 mm, T1 lesions were the most common, and acral lentiginous melanoma accounted for 42%. Thirteen patients (34%) had ulcerated lesions. Sentinel lymph node biopsy specimens of 25 patients identified four (16%) with metastatic disease. Surgical complications occurred in 12 patients, usually after skin graft or soft-tissue flap reconstruction. Systemic recurrence developed in six patients, four of whom also had regional recurrence. Conclusions: Most patients were elderly Caucasian women and most presented with early-stage disease, but diagnosis can be difficult and a subgroup presented with thick melanomas. Reconstructive surgical procedures had a high rate of complications; however, overall functional outcomes were good. Stage of cancer at diagnosis was associated with systemic metastases.

Studies comparing similar and sizable numbers of deep inferior epigastric perforator (DIEP) and pedicled transverse rectus abdominis musculocutaneous (TRAM) flap reconstructions are lacking. The authors hoped to determine whether the DIEP flap has advantages over the pedicled TRAM flap for breast reconstruction.

OBJECTIVE To determine the impact of sentinel lymph node (SLN) status and other risk factors on recurrence and overall survival in head and neck melanoma patients. DESIGN The SLN Working Group, based in San Francisco, Calif, with its 11 member centers, the John Wayne Cancer Institute, and The University of Texas M. D. Anderson Cancer Center pooled data on 629 primary head and neck melanoma patients who had selective sentinel lymphadenectomy. A total of 614 subjects were analyzable. All centers obtained internal review board approval and adhered to the Health Insurance Portability and Accountability Act of 1996 regulations. A Cox proportional hazards model was used to identify factors associated with overall and disease-free survival. SETTING Tertiary care medical centers. MAIN OUTCOME MEASURE Clinical outcome of head and neck melanoma patients undergoing selective sentinel lymphadenectomy. RESULTS Overall, 10.1% (n = 62) of the subjects had at least 1 positive node. Subjects with positive SLN status had significantly thicker tumors (mean thickness, 2.8 vs 2.1 mm; P&lt;.001), and were more likely to have ulcerated tumors (P = .004). During the median follow-up of 3.3 years, the overall mortality from head and neck melanoma was 10%, with more than 20% experiencing at least 1 recurrence. Multivariate analysis showed that tumor site was an independent predictor of mortality; location on the scalp had a more than 3-fold (P&lt;.001) greater mortality than tumors on the face. Tumor thickness was also an independent predictor of overall survival, and SLN status was the most important predictor of disease-free survival in the multivariate model (P&lt;.001). Tumors on the scalp had the highest rate of recurrence, while those on the neck had the lowest. Tumor ulceration was the significant predictor of time to recurrence or disease-free survival (P&lt;.001). CONCLUSION In this multicenter study, SLN status and other risk factors have an effect on recurrence and/or overall survival.Arch Otolaryngol Head Neck Surg. 2006;132:370-373--

The authors retrospectively reviewed the computerized records of 71 women undergoing 80 deep inferior epigastric perforator (DIEP) flap reconstructions after mastectomy over a 1-year period. There were 33 normal, 26 overweight, and 12 obese patients. No statistically significant difference in flap complications was found between groups. Overall fat necrosis rates were 11.4 percent for the normal-weight patients, 6.7 percent for the overweight patients, and 6.7 percent for the obese patients. Postoperative hospital time was similar for all groups. The occurrence of abdominal wall fascial laxity was uncommon and similar for all groups. Large (>900 g) reconstructions were completed without prohibitive complications in the reconstruction flap. The DIEP flap represents a significant advance in autologous breast tissue reconstruction. Although concerns regarding fat necrosis rates in DIEP flaps have been voiced, the authors did not see an increasing rate of fat necrosis in their overweight and obese patients, and their overall rate of fat necrosis is comparable to rates reported for free transverse rectus abdominis myocutaneous (TRAM) flaps. Also, increasing body mass index did not seem to affect the rate of delayed complications of the abdominal wall, such as abdominal wall hernia or bulging. Although it was not statistically significant, the authors did observe a trend toward increased wound-healing complications with increasing body mass index. Their data also support the claim that the complete sparing of the rectus abdominis muscles afforded by the DIEP flap avoids abdominal wall fascial bulging or defects often seen in obese TRAM reconstruction patients. Because flap and wound complication rates are similar or superior to those of other autologous tissue reconstruction techniques and the occurrence of abdominal wall defects is all but eliminated, the DIEP flap likely represents the preferred autologous breast reconstruction technique for overweight and obese patients.

Diaphragm disease of the small intestine is part of the spectrum of diseases associated with injury to the gastrointestinal tract induced by nonsteroidal anti-inflammatory drugs. Standard endoscopy or contrast studies of the small intestine rarely identify these lesions. The diagnosis usually is established at the time of surgery. We report the case of a 72-year-old woman with obscure gastrointestinal bleeding and intermittent obstruction of the small intestine who had had multiple hospitalizations and extensive testing. The patient had been treated with nonsteroidal anti-inflammatory drugs for osteoarthritis. A radiograph of the small intestine with barium contrast revealed no abnormalities, so capsule endoscopy was performed. Capsule endoscopy showed multiple small intestinal strictures beyond which the capsule could not pass. After the patient experienced continued symptoms suggestive of intermittent partial obstruction of the small intestine, computed tomography showed the capsule within a dilated loop of intestine adjacent to a stricture. After 9 days of conservative medical therapy and worsening symptoms, the patient required an exploratory laparotomy. The capsule was located in a 12-cm segment of intestine with 4 diaphragmlike lesions. Pathologic study found submucosal lesions with features identical to those of neuromuscular and vascular hamartoma (eg, mature, reactive tissue elements of smooth muscle, dense fibrous tissue, and nerve tissue bundles with scattered ganglion cells and vessels). No manifestations of Crohn disease were evident. This case represents the first diagnosis with capsule endoscopy of diaphragm disease of the small intestine with pathologic features of neuromuscular and vascular hamartoma.

Apophysomyces elegansis an environmental fungus related to other well-known agents of zygomycosis. We report a case of locally invasive A eleganssoft tissue infection resulting from the application of a skin patch to test for snapdragon sensitivity. The infection was limited to skin and soft tissue, and treatment consisted of local débridement and liposomal amphotericin B. Outcome was successful.

Simultaneous deregulation of both Wnt and ErbB growth factors has previously been shown to result in the cooperative induction of mammary gland tumors. Using the murine mammary tumor virus (MMTV)-Wnt-1 transgenic model of mammary carcinoma, we have identified an unvarying association between β-catenin and epidermal growth factor receptor/c-Neu (ErbB1/ErbB2) heterodimers in mammary gland tumors, indicating a requirement for ErbB signaling in Wnt-mediated tumorigenesis. Expansion of these observations to a second transgenic model, MMTV-c-Neu, demonstrated similar tumor-specific interactions, including an ErbB1 ligand-inducible phosphorylation of both β-catenin and c-Neu. Direct relevance of these findings to human breast cancer was established upon examination of a set of human infiltrating ductal breast adenocarcinoma and lymph node metastasis tissues taken at surgery. These data revealed increased levels of β-catenin in tumors and metastases versusnormal breast as well as an association between β-catenin and c-Neu that measurably occurs only in neoplasia, most strongly in metastatic lesions. These studies have identified a seemingly indispensable interaction between β-catenin and epidermal growth factor receptor/c-Neu heterodimers in Wnt-1-mediated breast tumorigenesis that may indicate a fundamental signaling event in human metastatic progression.

A total of 12 patients with stage 4 renal cell carcinoma and primary renal tumors in situ was entered into a pilot study using treatment with interleukin-2 and α-interferon followed by radical nephrectomy. Of the patients 11 underwent nephrectomy after an initial course of immunotherapy. Ten patients were able to receive a second course of immunotherapy given after nephrectomy. One patient achieved a complete response of lung and mediastinal metastases without any change in the primary renal tumor but after nephrectomy the patient remained in complete remission for greater than 11 months. A total of 3 patients achieved a partial response at some extrarenal sites but they had progression elsewhere. Toxicity was similar to previous experience with this immunotherapy regimen. Therefore, we demonstrated that metastatic tumor regression is possible with primary renal tumors in situ and that aggressive interleukin-2-based immunotherapy can be tolerated in the presence of a large renal tumor.

We report the occurrence of a refractory infection caused by the “rapidly growing” nontuberculous mycobacterium, Mycobacterium fortuitum, after incisional hernia repair using synthetic mesh. The patient had previously undergone three herniorrhaphies incorporating polypropylene mesh. Multiple surgical debridements were required, along with complete removal of all the mesh, to eradicate the infection. Prolonged antimicrobial therapy with sulfamethoxazole, an agent active against the patient's isolate, was also used. Although this atypical mycobacterium has been reported to cause a variety of infections, including many types of periprosthetic infections, this case represents successful treatment of M. fortuitum infecting abdominal wall mesh.

A robust personalized ctDNA test, TARDIS, achieves high accuracy for residual disease after completion of neoadjuvant therapy.

Introduction: Splenic trauma is a rare and potentially fatal complication of colonoscopy. Surgical treatment is required in many cases, but conservative management should be used when possible. Results and discussion: The authors report a case of splenic trauma secondary to colonoscopy in an elderly women who was successfully treated conservatively. They also detail other cases reported in the literature and discuss the risk factors for splenic injury and the benefits of using a conservative approach. Conclusion: Splenic trauma should be suspected in every patient who presents with abdominal pain following colonoscopy, especially those who are hemodynamically unstable or demonstrate an acute drop in hematocrit level. In cases where splenic trauma is identified early, the success rate of nonoperative treatment is increased considerably. [ABSTRACT FROM AUTHOR]

We present a simple method to dilate ureteral strictures, which was performed in 7 patients with metastatic cancer (1 breast, 1 lymphoma, 2 ovarian and 3 colorectal tumors) who presented with newly discovered obstruction in the distal ureter. The obstruction was due to tumor in the pelvis in 5 patients and to pelvic radiotherapy in 2. A 0.035-inch guide wire was passed beyond the stricture cystoscopically. In each case a double pigtail stent could not be passed beyond the stricture over the guide wire. The strictures were then dilated with progressively larger Van Andel catheters passed over the guide wire through the cystoscope. Following dilation a 7.5F to 8.5F soft double pigtail catheter was easily advanced. All patients had good drainage on followup radiographic studies. The method is presented as an alternative to balloon dilation of lower ureteral strictures when the goal is placement of an adequate diameter indwelling ureteral stent.